Biological activity is typically conferred by a set of structural features in a molecule that is recognized at a biological target, e.g., a receptor site. These features include structural steric and electronic features, and the set of such features is termed a “pharmacophore.” Certain natural products possess potent and selective biological activity, and a mutual interplay exists between natural products and the medicinal and biological sciences, as well as organic chemistry. Isolated natural products have provided a vast source of disease modulating drugs and efficient tools for studying biological phenomenon.
In order to fully explore the effects of various natural products on the increasing number of biological targets, it is necessary to develop synthetic methodologies that provide natural product analogs efficiently and in quantifiable yields.
Recently, there has been a keen interest in developing syntheses of Erythrina alkaloids and their analogs. The homologous [6.6.5.6]-erythrinan ring system (illustrated below) exhibits diverse biological activity (Reimann, E. Prog. Org. Nat. Prod. 2007, 88, 1; Bentley, K. W. Nat. Prod. Rep. 2004, 21, 395).

Bile acids are amphipathic molecules that solubilize dietary lipids and promote the absorption of the lipids into the digestive tract. Bile acids may also act as signaling molecules, which activate signaling networks within the body, such as TGR5 (a G-protein-coupled receptor), and members of the nuclear hormone receptor superfamily (e.g. farnesoid-X-receptor, constitutive androstane receptor, pregnane X receptor, and vitamin D receptor). TGR5 belongs to the rhodopsin-like superfamily of GPCRs that transduces signals through the Gs protein. TGR5 is expressed in gall bladder tissue, ileum tissue, and colon tissue and it has been found to regulate energy expenditure by increasing basal metabolism. In particular, TGR5 ligation may stimulate cAMP synthesis and/or activate the mitogen-activated protein kinase pathway. TGR5 activation causes internalization of the receptor and increased intracellular cAMP, which can then activate protein kinase A. TGR5 may also be involved in regulating glucose homeostasis and regulating intrahepatic microcirculation. Given TGR5's important biological activity, it has emerged as an important target for treating disorders of lipid and glucose homeostasis.
Efforts to develop TGR5 agonists have so far been focused on exploiting the structure of natural ligands, such as LCA, TLCA, and oleanolic acid. In addition, the 23-alkyl-substituted and 6,23-alkyl disubstituted derivatives of CDCA have been shown to be agonists of TGR5. While these compounds can act as TGR5 agonists, these steroidal TGR5 ligands can be toxic and levels of their administration must be carefully monitored to prevent deleterious effects. There also exist semi-synthetic non-steroidal TGR5 agonists, such as 6-methyl-2-oxo-4-thiophen-2-yl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid benzyl esters, quinazolinones, imidazole[1,2-a][1,2]diazepin, and quinolines. Despite these known agonists, there exists a need in the art for TGR5 agonists that are safe for administration and that effectively target either TGR5 receptors, bile acid receptors, and/or G-protein-coupled receptors.